The present invention relates to quinazoline derivatives that are alpha-1 adrenergic receptor antagonists, and in particular to certain quinazoline derivatives that are selective alpha-1B adrenergic receptor antagonists, and associated pharmaceutical compositions, methods for use as therapeutic agents, and methods of preparation thereof.
Alpha-1 adrenergic receptors are G-protein coupled transmembrane receptors that mediate various actions of the sympathetic nervous system through the binding of the catecholamines, epinephrine and norepinephrine. Currently, several subtypes of the alpha-1 adrenergic receptors are known to exist for which the genes have been cloned: alpha-1A (previously known as alpha-1C), alpha-1B and alpha-1D. The existence of an additional subtype, the alpha-1L adrenergic receptor subtype, has been proposed; however, the gene for the alpha-1L adrenergic receptor subtype has yet to be cloned. Although these subtypes can be pharmacologically distinguished, existing subtype-selective compounds are only moderately specific and may interact with more than one alpha-1 adrenergic receptor subtype (See Giardina, D., et al., J. Med. Chem., 1996, 39:4602-4607).
Non-selective alpha-1 adrenoceptor antagonists have been used to treat lower urinary tract symptoms associated with benign prostatic hyperplasia (BPH). Further, alpha-1 adrenoceptor antagonists can be effective in reducing or alleviating urinary tract disorders and/or symptoms thereof, such as pelvic hypersensitivity, overactive bladder, urinary frequency, nocturia, urinary urgency, detrusor hyperreflexia, outlet obstruction, prostatitis, incontinence, urge incontinence, urethritis, prostatodynia, idiopathic bladder hypersensitivity, and the like. Accordingly, therapeutic use of nonselective alpha-1 adrenergic receptor antagonists must be carefully monitored as such antagonists can produce significant undesirable side effects such as postural hypotension, sedation or depression, increased gastrointestinal motility and diarrhea, impaired ability to ejaculate, nasal stuffiness, akinesia and the like.
Compounds that interact more selectively with a particular alpha-1 adrenergic receptor subtype may prove clinically useful in providing more selective treatment of conditions and diseases associated with abnormal activity at the receptor subtype. For example, alpha-1 adrenergic receptor antagonists that can selectively ameliorate nociceptive and/or neurogenic pain without affecting blood pressure or causing postural hypotension, dizziness or syncope, are desirable.
Selective alpha-1B adrenergic receptor antagonists can also be useful in the treatment of CNS disorders including, but not limited to, anxiety, sleep disorders, and schizophrenia (see, e.g., Bakshi, et al. (1999) Neuroscience 92:113-121; Carasso, et al. (1998) Neuropharmacol. 37:401-404; and Acosta-Martinez, et al. (1999) Neurochem. Int. 35:383-391). Recently, the non-selective alpha-1 adrenergic receptor antagonist prazosin has also been useful in the amelioration of combat trauma nightmares in veterans with posttraumatic stress disorder (see e.g., Raskind, et al. (2000) J. Clin. Psychiatry 61(2), 129-133).
Because of their ability to selectively antagonize alpha-1B adrenergic receptors, the compounds of this invention lack the undesirable effects of non-selective alpha-1 adrenergic receptor antagonists such as prazosin, terazosin, and doxazosin.
U.S. patent application Ser. No. 09/521,185 (Coffen, et al.), refers to certain oxazolone derivatives as alpha-1B adrenergic receptor antagonists.
PCT Application Publication WO97/11698 (assigned to Merck), refers to certain selective alpha-1B adrenergic receptor antagonists used in the treatment of hypertension.
PCT Application Publication WO97/23462 and U.S. Pat. No. 6,169,093 (assigned to Pfizer), refer to certain quinoline and quinazoline compounds useful in the treatment of benign prostatic hyperplasia.
Raskind, et al., J. Clin. Psychiatry 2000, 61(2), 129-133, refer to the use of prazosin to ameliorate combat trauma nightmares in veterans with posttraumatic stress disorder.
Brooks, et al., Proc. West. Pharmacol. Soc. 1999, 42, 67-69, refer to clozapine and other antipsychotic drugs for interaction with human alpha-1 adrenergic receptor subtypes.
Acosta-Martinez, et al., Neurochem. Int. 1999 35:383-391, refer to the localization of alpha-1B adrenergic receptor in female rat brain regions involved in stress and neuroendocrine function.
Bakshi, et al., Neuroscience 1999, 92:113-121, refer to alpha-1 adrenergic receptors mediating sensorimotor gating deficits which are thought to result in sensory inundation, cognitive fragmentation and attentional deficits, all of which are features common to schizophrenia and drug-induced psychotic states.
Carasso, et al., Neuropharmacol. 1998, 37:401-404, refer to the role of alpha-1 adrenoceptors in the psychotherapeutic actions of certain antipsychotics.
Giardina, et al., J. Med. Chem. 1996, 39, 4602-4607, refer to the synthesis of cyclazosin enantiomers and their activity as alpha-1B antagonists.
Patane, et al., J. Med. Chem, 1998, 41,1205-1208, refer to L-765314 as a potent and selective alpha-1B antagonist.
Xie, et al., Soc. for Neuroscience Abstract, 1998, 24, 2089, refer to certain alpha-1B adrenergic receptor mRNA expression in rat DRG after spinal nerve injury.
Lee, et al., J. Neurophysiol. 1999, 81, 2226-2233, refer to certain receptor subtypes mediating the adrenergic sensitivity of pain behavior.
All publications, patents, and patent applications cited herein, whether supra or infra, are each hereby incorporated by reference in its entirety.
This invention relates to compounds comprising Formula (I): 
wherein:
R1 is hydrogen, or lower alkyl;
R2 is lower alkyl, heterocyclyl, heteroaryl, or aryl, all optionally substituted with lower alkyl, alkoxy, halogen, or cyano;
Rxe2x80x2 and Rxe2x80x3 are each independently lower alkyl;
A is hydrogen, xe2x80x94(CH2)0-1R3, xe2x80x94C(O)R3, xe2x80x94SO2R3, xe2x80x94C(O)OR3, xe2x80x94C(O)NR4R5, xe2x80x94SO2NR4R5, C(NR6)R3, or xe2x80x94C(NR6)NR4R5;
R3 is independently in each occurrence lower alkyl optionally substituted with halogen, amino, alkylamino, hydroxy, alkoxy, acyloxy, aminocarbonyl, alkoxycarbonylamino, nitro, or cyano; aryl; arylalkyl; heteroaryl; heteroarylalkyl; cycloalkyl; cycloalkylalkyl; heterocyclyl; or heterocyclylalkyl;
R4 and R5 are each independently hydrogen or R3 as defined above;
R4 and R5 taken together with the nitrogen to which they are attached form a 5- to 7-membered ring, optionally incorporating one or two additional ring heteroatoms
R6 is hydrogen, lower alkyl or cyano; and chosen from N, S, or O;
n is an integer from 0 to 2 inclusive and m is an integer from 0 to 3 inclusive, wherein m+n is equal to or larger than 2;
or acceptable prodrug, salt or solvate thereof.
In another aspect, the invention relates to pharmaceutical compositions containing a therapeutically effective amount of at least one compound of Formula (I), or acceptable prodrug, salt or solvate thereof, in admixture with at least one suitable carrier.
In another aspect, the invention further relates to a process which comprises reacting a compound having the formula 
wherein L is a leaving group,
with a compound of general formula 
to provide a compound of the general Formula (I) 
wherein Rxe2x80x2, Rxe2x80x3, R1, R2, m , n, and A are as defined herein.
In another embodiment, the invention further relates to a process which comprises reacting a compound having the formula: 
with a compound of the general formula A-L, wherein L is a leaving group, to provide a compound of general Formula (I) 
wherein Rxe2x80x2, Rxe2x80x3, R1, R2, m, n and A are as defined herein.
Definitions
Unless otherwise stated, the following terms used in this Application, including the specification and claims, have the definitions given below. It must be noted that, as used in the specification and the appended claims, the singular forms xe2x80x9ca,xe2x80x9d xe2x80x9can,xe2x80x9d and xe2x80x9cthexe2x80x9d include plural referents unless the context clearly dictates otherwise.
xe2x80x9cLower alkylxe2x80x9d means the monovalent linear, branched or cyclic saturated hydrocarbon radical, having from one to six carbon atoms inclusive, unless otherwise indicated. Examples of lower alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, sec-butyl, tert-butyl, n-butyl, n-pentyl, n-hexyl, cyclopropylmethyl, and the like.
xe2x80x9cLower alkylenexe2x80x9d means the divalent linear or branched saturated hydrocarbon radical, having from one to six carbons inclusive, unless otherwise indicated. Examples of lower alkylene radicals include, but are not limited to, methylene, ethylene, propylene, 2-methyl-propylene, butylene, 2-ethylbutylene, and the like.
xe2x80x9cAlkoxyxe2x80x9d means the radical xe2x80x94Oxe2x80x94R, wherein R is a lower alkyl radical as defined herein. Examples of alkoxy radicals include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like.
xe2x80x9cArylxe2x80x9d means the monovalent aromatic hydrocarbon radical consisting of one individual ring, or one or more fused rings in which at least one ring is aromatic in nature, which can optionally be substituted with one or more, preferably one or two, substituents selected independently from hydroxy, cyano, lower alkyl, lower alkoxy, allcylthio, halogen, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylarninosulfonyl, arylaminosulfonyl, alkylcarbonylamino, arylcarbonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkylsulfonylamino, or arylsulfonylamino unless otherwise indicated. Alternatively, two adjacent atoms of the aryl ring may be substituted with a methylenedioxy or ethylenedioxy group. Examples of aryl radicals include, but are not limited to, phenyl, naphthyl, biphenyl, 2,3-dihydrobenzo[1,4]dioxin-2-yl,2,3-dihydrobenzo[1,4]dioxin-5-yl,6-methyl-benzo[1,3]dioxol-5-yl, 1,3-benzodioxolyl, indanyl, 2,4-dimethyl-phenyl, 2-cyano-phenyl and the like.
xe2x80x9cArylalkylxe2x80x9d (or xe2x80x9caralkylxe2x80x9d) means the radical RaRbxe2x80x94, wherein Ra is an aryl radical as defined herein, and Rb is a lower alkylene radical as defined herein. Examples of arylalkyl radicals include, but are not limited to, benzyl, phenylethyl, 3-phenylpropyl, and the like.
xe2x80x9cCycloalkylxe2x80x9d means the monovalent saturated carbocyclic radical consisting of one or more rings, which can optionally be substituted with one or more, preferably one or two substituents selected independently from hydroxy, cyano, lower alkyl, lower alkoxy, alkylthio, halogen, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylcarbonylamino, alrylcarbonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkylsulfonylamino, or arylsulfonylamino, unless otherwise indicated. Examples of cycloalkyl radicals include, but are not limited to, cyclopropyl, cyclobutyl, 3-ethylcyclobutyl, cyclopentyl, cycloheptyl, and the like.
xe2x80x9cCycloalkylalkylxe2x80x9d means the radical RaRbxe2x80x94, wherein Ra is a cycloalkyl radical as defined herein, and Rb is an lower alkylene radical as defined herein. Examples of cycloalkylalkyl radicals include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclohexylmethyl, cyclopentylethyl, and the like.
xe2x80x9cHeteroarylxe2x80x9d means the monovalent aromatic cyclic radical having one or more rings, preferably one to three rings, of four to eight atoms per ring, incorporating one, two, or three heteroatoms within the ring (chosen from nitrogen, oxygen, or sulfur) which can optionally be substituted with one or more, preferably one or two substituents selected independently from hydroxy, cyano, lower alkyl, lower alkoxy, alkylthio, halogen, halogenalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylcarbonylamino, alrylcarbonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkylsulfonylamino, or arylsulfonylamino, unless otherwise indicated. Examples of heteroaryl radicals include, but are not limited to, imidazolyl, oxazolyl, thiazolyl, pyrazinyl, thienyl, furanyl, pyridinyl, pyrimidinyl, pyridinazyl, pyrrolyl, quinolinyl, isoquinolinyl, benzofuryl, indazolyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, naphthyridinyl, and the like.
xe2x80x9cHeteroarylalkylxe2x80x9d (or xe2x80x9cheteroaralkylxe2x80x9d) means the radical of the formula RaRbxe2x80x94, wherein Ra is a heteroaryl radical as defined herein, and Rb is a lower alkylene radical as defined herein. Examples of heteroarylalkyl radicals include, but are not limited to, 2-pyridinylmethyl, 3-furanylethyl, 2-thienylalkyl, and the like.
xe2x80x9cHeterocyclylxe2x80x9d means the monovalent saturated cyclic radical, consisting of one or more rings, preferably one to two rings, of three to eight atoms per ring; incorporating one, two, or three ring heteroatoms (chosen from N, O or S(O)0-2), which can optionally be substituted with one or more, preferably one or two substituents selected independently from hydroxy, oxo, cyano, lower alkyl, lower alkoxy, alkylthio, halogen, halogenalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylcarbonylamino, arylcarbonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkylsulfonylamino, or arylsulfonylamino, unless otherwise indicated. Examples of heterocyclyl radicals include, but are not limited to, morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydropyranyl, thiomorpholinyl, and the like.
xe2x80x9cHeterocycloalkylxe2x80x9d (or xe2x80x9cheterocyclylalkylxe2x80x9d) means the radical of the formula RaRb, wherein Ra is a heterocyclic radical as defined herein, and Rb is a lower alkylene radical as defined herein. Examples of heterocycloalkyl radicals include, but are not limited to, 1-piperazinylmethyl, 2-morpholinomethyl, and the like.
xe2x80x9cHalogenxe2x80x9d, xe2x80x9chaloxe2x80x9d, or xe2x80x9chalidexe2x80x9d means the radical fluoro, bromo, chloro, and/or iodo.
xe2x80x9cHalogenalkylxe2x80x9d or xe2x80x9chaloalkylxe2x80x9d means the lower alkyl radical as defined herein substituted in any position with one or more halogen atoms as defined herein. Examples of haloalkyl radicals include, but are not limited to, 1,2-difluoropropyl, 1,2-dichloropropyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, and the like.
xe2x80x9cHydroxyalkylxe2x80x9d means the lower alkyl radical as defined herein, substituted with one or more hydroxy groups. Examples of hydroxyalkyl radicals include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1,3-dihydroxy-2-propyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl, and 2-(hydroxymethyl)-3-hydroxypropyl, and the like.
xe2x80x9cAlkylaminoxe2x80x9d means the radical xe2x80x94NRaRbxe2x80x3, wherein Ra is a lower alkyl radical as defined herein, and Rb is hydrogen or lower alkyl as defined herein. Examples of alkylamino radicals include, but are not limited to, methylamino, (1-methylpropyl)amino, dimethylamino, methylethylamino, diethylamino, N,N-hydroxyethyl-ethylamino, N,N-methoxyethyl-ethylamino and the like.
xe2x80x9cAcyloxyxe2x80x9d means the radical RC(O)Oxe2x80x94, wherein R is a lower alkyl radical as defined herein. Examples of acyloxy radicals include, but are not limited to, acetoxy, propionyloxy, and the like.
xe2x80x9cAlkylcarbonylxe2x80x9d means the radical RC(O)xe2x80x94, wherein R is an optionally substituted lower alkyl radical as defined herein. Examples of alkylcarbonyl radicals include, but are not limited to, formyl, acetyl, propionyl, n-butyryl, sec-butyryl, t-butyryl, iso-propionyl and the like.
xe2x80x9cAlkoxycarbonylxe2x80x9d or xe2x80x9calkyl esterxe2x80x9d means the radical xe2x80x94C(O)xe2x80x94Oxe2x80x94R, wherein R is a lower alkyl radical as defined herein. Examples of alkoxycarbonyl radicals include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, sec-butoxycarbonyl, isopropyloxycarbonyl, and the like.
xe2x80x9cAminocarbonylxe2x80x9d means the radical xe2x80x94C(O)NRaRb, wherein Ra and Rb are independently from each other hydrogen or lower alkyl as defined herein. Examples of alkylaminocarbonyl include, but are not limited to methylaminocarbonyl, dimethylaminocarbonyl, t-butylaminocarbonyl, n-butylaminocarbonyl, iso-propylaminocarbonyl and the like.
xe2x80x9cAlkoxycarbonylaminoxe2x80x9d means the radical xe2x80x94NC(O)OR, wherein R is lower alkyl as defined herein. Examples of alkoxycarbonylamino include, but are not limited to t-butyloxycarbonylamino, methoxycarbonylamino and the like.
xe2x80x9cOptionally substitutedxe2x80x9d means that a group may or may not be substituted with one or more, preferably one or two substitutents independently selected from the specified group. For example phenyl optionally substituted with lower alkyl, alkoxy, halogen or cyano means that the phenyl group may or may not be substituted at any position with one or more, preferably one or two substituents independently selected from the group lower alkyl, alkoxy, halogen or cyano.
xe2x80x9cLeaving groupxe2x80x9d means the group with the meaning conventionally associated with it in synthetic organic chemistry, i.e., an atom or group displaceable by a nucleophile. Examples of leaving groups include, but are not limited to, halogen, alkyl- or arylsulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy, thiomethyl, benzenesulfonyloxy, tosyloxy, and thienyloxy, dihalophosphinoyloxy, optionally substituted benzyloxy, isopropyloxy, acyloxy, and the like.
xe2x80x9cProtective groupxe2x80x9d or xe2x80x9cprotecting groupxe2x80x9d means the group which selectively blocks one reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site in the meaning conventionally associated with it in synthetic chemistry. Examples of protecting groups can be found in T. W. Greene et al., Protective Groups in Organic Chemistry, (J. Wiley, 2nd ed. 1991) and Harrison et al., Compendium of Synthetic Organic Methods, Vol. 1-8 (J. Wiley and Sons 1971-1996).
xe2x80x9cAmino-protecting groupxe2x80x9d means the protecting group that refers to those organic groups intended to protect the nitrogen atom against undesirable reactions during synthetic procedures and includes, but is not limited to, benzyl, benzyloxycarbonyl (carbobenzyloxy, CBZ), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC), trifluoroacetyl, and the like. It is preferred to use either BOC or CBZ as the amino-protecting group because of the relative ease of removal, for example by mild acids in the case of BOC, e.g., trifluoroacetic acid or hydrochloric acid in ethyl acetate; or by catalytic hydrogenation in the case of CBZ.
xe2x80x9cDeprotectionxe2x80x9d or xe2x80x9cdeprotectingxe2x80x9d means the process by which a protective group is removed after the selective reaction is completed. Certain protective groups may be preferred over others due to their convenience or relative ease of removal.
xe2x80x9cInert organic solventxe2x80x9d or xe2x80x9cinert solventxe2x80x9d means the solvent inert under the conditions of the reaction being described in conjunction therewith, including for example, benzene, toluene, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, chloroform, methylene chloride or dichloromethane, dichloroethane, diethyl ether, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, tert-butanol, dioxane, pyridine, and the like. Unless specified to the contrary, the solvents used in the reactions of the present invention are inert solvents.
xe2x80x9cIsomerismxe2x80x9d means compounds that have identical molecular formulae but that differ in the nature or the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed xe2x80x9cstereoisomersxe2x80x9d. Stereoisomers that are not mirror images of one another are termed xe2x80x9cdiastereoisomersxe2x80x9d, and stereoisomers that are non-superimposable mirror images are termed xe2x80x9cenantiomersxe2x80x9d, or sometimes optical isomers. A carbon atom bonded to four nonidentical substituents is termed a xe2x80x9cchiral centerxe2x80x9d.
xe2x80x9cChiral compoundxe2x80x9d means a compound with at least one chiral center. It has two enantiomeric forms of opposite chirality and may exist either as an individual enantiomer or as a mixture of enantiomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a xe2x80x9cracemic mixturexe2x80x9d. A compound that has more than one chiral center has 2nxe2x88x921 enantiomeric pairs, where n is the number of chiral centers. Compounds with more than one chiral center may exist as either an individual diastereomer or as a mixture of diastereomers, termed a xe2x80x9cdiastereomeric mixturexe2x80x9d. When chiral centers are present, the stereoisomers may be characterized by the absolute configuration (R or S ) of the chiral centers. Absolute configuration refers to the arrangement in space of the substituents attached to a chiral center. The substituents attached to a chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al. Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al. Angew. Chem. 1966, 78, 413; Cahn and Ingold J. Chem. Soc. (London) 1951, 612; Cahn et al. Experientia, 1956, 12, 81; Cahn et al., J. Chem. Educ., 1964, 41, 116).
xe2x80x9cAtropic isomersxe2x80x9d means the isomers owing their existence to restricted rotation caused by hindrance of rotation of large groups about a central bond.
xe2x80x9cSubstantially purexe2x80x9d means at least about 80 mole percent, more preferably at least about 90 mole percent, and most preferably at least about 95 mole percent of the desired enantiomer or stereoisomer is present compared to other possible configurations.
xe2x80x9cPharmaceutically acceptablexe2x80x9d means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use.
xe2x80x9cAcceptable saltxe2x80x9d of a compound means salt that possesses the desired pharmacological activity of the parent compound. Such salts include:
(1) an acid addition salt formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, dibenzoyl-L-tartaric acid, tartaric acid, p-toluene sulfonic acid, trimethylacetic acid, 2,2,2-trifluoroacetic acid, and the like; or
(2) a salt formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic or inorganic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.
The preferred acceptable salts are the salts formed from hydrochloric acid, and 2,2,2-trifluoroacetic acid. It should be understood that all references to acceptable salt include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same acid addition salt.
xe2x80x9cCrystal formsxe2x80x9d (or polymorphs) means crystal structures in which a compound can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystal forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate.
xe2x80x9cSolvatexe2x80x9d means solvent addition form that contains either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate, when the solvent is alcohol, the solvate formed is an alcoholate.
xe2x80x9cProdrugxe2x80x9d means a pharmacologically inactive form of a compound which is metabolized in vivo, e.g., by biological fluids or enzymes, by a subject after administration into a pharmacologically active form of the compound in order to produce the desired pharmacological effect. The prodrug can be metabolized before absorption, during absorption, after absorption, or at a specific site. Although metabolism occurs for many compounds primarily in the liver, almost all other tissues and organs, especially the lung, are able to carry out varying degrees of metabolism. Prodrug forms of compounds may be utilized, for example, to improve bioavailability, improve subject acceptability such as by masking or reducing unpleasant characteristics such as bitter taste or gastrointestinal irritability, alter solubility such as for intravenous use, provide for prolonged or sustained release or delivery, improve ease of formulation, or provide site-specific delivery of the compound. Reference to a compound herein includes prodrug forms of a compound. Prodrugs are described in The Organic Chemistry of Drug Design and Drug Action, by Richard B. Silverman, Academic Press, San Diego, 1992. Chapter 8: xe2x80x9cProdrugs and Drug delivery Systemsxe2x80x9d pp.352-401; Design of Prodrugs, edited by H. Bundgaard, Elsevier Science, Amsterdam, 1985; Design of Biopharmaceutical Properties through Prodrugs and Analogs, edited. by E. B. Roche, American Pharmaceutical Association, Washington, 1977; and Drug Delivery Systems, edited by R. L. Juliano, Oxford Univ. Press, Oxford, 1980.
xe2x80x9cSubjectxe2x80x9d means mammals and non-mammals. Mammals means any member of the mammalian class including, but not limited to, humans, non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, and swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice, and guinea pigs; and the like. Examples of non-mammals include, but are not limited to, birds, reptiles and the like.
xe2x80x9cTherapeutically effective amountxe2x80x9d means an amount of a compound that, when administered to a subject for treating a disease state, is sufficient to effect such treatment for the disease state. The xe2x80x9ctherapeutically effective amountxe2x80x9d will vary depending on the compound, and disease state being treated, the severity or the disease treated, the age and relative health of the subject, the route and form of administration, the judgement of the attending medical or veterinary practitioner, and other factors.
xe2x80x9cPharmacological effectxe2x80x9d as used herein encompasses effects produced in the subject that achieve the intended purpose of a therapy. In one preferred embodiment, a pharmacological effect means that primary indications of the subject being treated are prevented, alleviated, or reduced. For example, a pharmacological effect would be one that results in the prevention, alleviation or reduction of primary indications in a treated subject. In another preferred embodiment, a pharmacological effect means that disorders or symptoms of the primary indications of the subject being treated are prevented, alleviated, or reduced. For example, a pharmacological effect would be one that results in the prevention or reduction of primary indications in a treated subject.
xe2x80x9cDisease statexe2x80x9d means any disease, condition, symptom, or indication.
xe2x80x9cTreatingxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d of a disease state includes:
(1) preventing the disease state, i.e. causing the clinical symptoms of the disease state not to develop in a subject that may be exposed to or predisposed to the disease state, but does not yet experience or display symptoms of the disease state.
(2) inhibiting the disease state, i.e., arresting the development of the disease state or its clinical symptoms, or
(3) relieving the disease state, i.e., causing temporary or permanent regression of the disease state or its clinical symptoms.
xe2x80x9cSpecific alpha-1 adrenergic receptorxe2x80x9d as used herein, refers to a distinct member of the group or class of adrenoceptors, which may be selected from the human alpha-1A (previously known as alpha-1C), alpha-1B, alpha-1D, and alpha-1L adrenergic receptors. Preferred species from which may be derived or isolated alpha1-adrenergic receptor subtype polypeptides, genes encoding and alpha-1 adrenergic receptor subtype, and/or cells, tissues and organs that express one or more alpha-1 adrenergic receptor subtype, include human, bovine, rat, murine, porcine, and the like. A more preferred species is human.
xe2x80x9cAlpha-1B adrenergic receptorxe2x80x9d or xe2x80x9calpha-1B adrenoceptorxe2x80x9d means the specific alpha1-adrenoceptor expressed in numerous tissues, most notably in the liver, heart, and cerebral cortex. Alpha-1B adrenoceptors are also present in areas of the spinal cord, which receive input from sympathetic neurons originating in the pontine micturition center.
xe2x80x9cAntagonistxe2x80x9d means a molecule, such as a compound, a drug, an enzyme inhibitor, or a hormone, that diminishes or prevents the action of another molecule or receptor site.
xe2x80x9cTraumaxe2x80x9d means any wound or injury. Trauma can produce, for example, acute and/or chronic pain, inflammatory pain, and neuropathic pain.
xe2x80x9cPainxe2x80x9d means the more or less localized sensation of discomfort, distress, or agony, resulting from the stimulation of specialized nerve endings. There are many types of pain, including, but not limited to, lightning pains, phantom pains, shooting pains, acute pain, inflammatory pain, neuropathic pain, complex regional pain, neuralgia, neuropathy, and the like (Dorland""s Illustrated Medical Dictionary, 28th Edition, W. B. Saunders Company, Philadelphia, Pa.). The goal of treatment of pain is to reduce the degree of severity of pain perceived by a treatment subject.
xe2x80x9cDisorders of the urinary tractxe2x80x9d or xe2x80x9curopathyxe2x80x9d used interchangeably with xe2x80x9csymptoms of the urinary tractxe2x80x9d means the pathologic changes in the urinary tract. Examples of urinary tract disorders include, but are not limited to, incontinence, benign prostatic hypertrophy (BPH), prostatitis, detrusor hyperreflexia, outlet obstruction, urinary frequency, nocturia, urinary urgency, overactive bladder, pelvic hypersensitivity, urge incontinence, urethritis, prostatodynia, cystitis, idiophatic bladder hypersensitivity, and the like.
xe2x80x9cOveractive bladderxe2x80x9d or xe2x80x9cdetrusor hyperactivityxe2x80x9d includes, but is not limited to, the changes symptomatically manifested as urgency, frequency, altered bladder capacity, incontinence, micturition threshold, unstable bladder contractions, sphincteric spasticity, detrusor hyperreflexia (neurogenic bladder), detrusor instability, and the like.
xe2x80x9cOutlet obstructionxe2x80x9d includes, but is not limited to, benign prostatic hypertrophy (BPH), urethral stricture disease, tumors, low flow rates, difficulty in initiating urination, urgency, suprapubic pain, and the like.
xe2x80x9cOutlet insufficiencyxe2x80x9d includes, but is not limited to, urethral hypermobility, intrinsic sphincteric deficiency, mixed incontinence, stress incontinence, and the like.
xe2x80x9cPelvic Hypersensitivityxe2x80x9d includes, but is not limited to, pelvic pain, interstitial (cell) cystitis, prostadynia, prostatis, vulvadynia, urethritis, orchidalgia, overactive bladder, and the like.
xe2x80x9cDisease states associated with the Central Nervous System (CNS)xe2x80x9d or xe2x80x9cCNS disease statesxe2x80x9d mean neurological and/or psychiatric changes in the CNS, e.g., brain and spinal cord, which manifest in a variety of symptoms. Examples of CNS disease states include, but are not limited to, cerebrovascular deficiency; psychoses including paranoia and schizophrenia; attention deficiency and autism; bipolar disorder; anxiety disorders including anticipatory anxiety (e.g., prior to surgery, dental work and the like); obsessive/compulsive disorders; posttraumatic stress disorders; eating disorders including anorexia and bulimia; sleep disorders; convulsive disorders including epilepsy and withdrawal from addictive substances; cognitive diseases including Parkinson""s disease and dementia; depression; mania; seasonal affective disorder (SAD); convulsions and anxiety caused by withdrawal from addictive substances such as opiates, benzodiazepines, nicotine, alcohol, cocaine, and other substances of abuse; and improper thermoregulation.
The naming and numbering of the compounds of this invention is illustrated below: 
In general, the nomenclature used in this Application is based on Autonom(trademark) v. 4.0, a Beilstein Institute computerized system for the generation of IUPAC systematic nomenclature.
For example, a compound of Formula (I) wherein R1 is xe2x80x94CH3, R2 is phenyl, m is 2, n is 2, and A is xe2x80x94COR3, wherein R3 is xe2x80x94(CH2)3OH is named:
1-(4-{[(4-amino-6,7-dimethoxy-quinazolin-2-yl)-methyl-amino]-methyl}-4-phenyl-piperidin-1-yl)-4-hydroxy-butan-1-one.
Similarly, a compound of Formula (I) wherein R1 is xe2x80x94CH3, R2 is phenyl, m is 2, n is 2, and A is xe2x80x94COR3, wherein R3 is furanyl is named:
1-{4-[(4-amino-6,7-dimethoxy-quinazolin-2-ylamino)-methyl]-4-phenyl-piperidin-1-yl}-1-furan-2yl-methanone
A compound of Formula (I) wherein R1 is xe2x80x94CH3, R2 is phenyl, m is 2, n is 2, and A is xe2x80x94SO2R3, wherein R3 is isopropyl is named:
6,7-dimethoxy-N2-methyl-N2-[1xe2x80x2-(propane-2-sulfonyl)-2xe2x80x2,3xe2x80x2,5xe2x80x2,6xe2x80x2-tetrahydro-1xe2x80x2H-[2,4xe2x80x2]bipyridinyl-4xe2x80x2-ylmethyl]-quinazoline-2,4-diamine.
Additionally a compound of Formula (I) wherein R1 is xe2x80x94CH3, R2 is phenyl, m is 2, n is 2, and A is xe2x80x94CH2R3, wherein R3 is benzyl is named:
1-(4-{[(4-amino-6,7-dimethoxy-quinazolin-2-yl)-methyl-amino]-methyl}-4-phenyl-piperidin-1-yl)-2-phenyl-ethanone.
Among compounds of the present invention set forth in the Summary of the Invention, certain compounds of Formula (I), or acceptable prodrug, salt or solvate thereof, are preferred:
R1 is hydrogen or lower alkyl; preferably, R1 is lower alkyl; and even more preferably, R1 is methyl.
R2 is lower alkyl, aryl, heterocyclyl, heteroaryl or aryl, all optionally substituted with lower alkyl, alkoxy, halogen or cyano; more preferably, R2 is aryl optionally substituted with lower alkyl, alkoxy, halogen or cyano; and even more preferably R2 is phenyl optionally substituted with lower alkyl, alkoxy, halogen or cyano.
Rxe2x80x2 and Rxe2x80x3 are each independently lower alkyl; more preferably Rxe2x80x2 and Rxe2x80x3 are each independently methyl.
A is preferably hydrogen, xe2x80x94(CH2)0-1R3, xe2x80x94C(O)R3, SO2R3, xe2x80x94C(O)OR3, xe2x80x94C(O)NR4R5, xe2x80x94SO2NR4R5, xe2x80x94C(NR )R3 or C(NR6)NR4R5; more preferably xe2x80x94(CH2)0-1R3, xe2x80x94C(O)R3, SO2R3, xe2x80x94C(O)NR4R5, xe2x80x94SO2NR4R5, xe2x80x94C(NR6)R3, or xe2x80x94C(NR6)NR4R5, and even more preferably, A is xe2x80x94C(O)R3, or xe2x80x94SO2R3.
R3 is independently in each occurrence lower alkyl, optionally substituted with halogen, amino, alkylamino, hydroxy, alkoxy, acyloxy, aminocarbonyl, alkoxycarbonylamino, nitro, or cyano; aryl; arylalkyl; heteroaryl; heteroarylalkyl; cycloalkyl; cycloalkylalkyl; heterocyclyl; or heterocyclylalkyl; more preferably, R3 is lower alkyl or cycloalkyl optionally substituted with halogen, amino, alkylamino, hydroxy, alkoxy, acyloxy, aminocarbonyl, alkoxycarbonylamino, nitro, or cyano; and even more preferably, R3 is independently in each occurrence lower alkyl optionally substituted with fluoro, hydroxy or alkoxy.
R4 and R5 are each independently from each other hydrogen, or R4 and R5 taken together with the nitrogen to which they are attached form a 5- to 7-membered ring, optionally incorporating one or two additional ring heteroatoms chosen from N, S, or O.
R6 is hydrogen, lower alkyl or cyano.
n is an integer ranging from 0 to 2 inclusive, and m is an integer from 0 to 3 inclusive, on condition that m+n is equal or larger than 2; more preferably n is 2 and m is 2.
Other preferred compounds of the present invention include the acceptable salts of the compounds of the present invention wherein the preferred pharmaceutically acceptable salts are formed from hydrochloric acid; or trifluoroacetic acid.
Exemplary particularly preferred compounds, or acceptable prodrug, salt or solvate thereof, include:
1-(4-{[(4-Amino-6,7-dimethoxy-quinazolin-2-yl)-methyl-amino ]-methyl}-4-phenyl-piperidin-1-yl)-1-cyclopropyl-methanone;
6,7-Dimethoxy-N2-methyl-N2-[4-phenyl-1-(propane-2-sulfonyl)-piperidin-4-ylmethyl]-quinazoline-2,4-diamine;
1-(4-{[(4-Amino-6,7-dimethoxy-quinazolin-2-yl)-methyl-amino]-methyl}-4-phenyl-piperidin-1-yl)-4,4,4-trifluoro-butan-1-one;
(S)-1-(4-{[(4-Amino-6,7-dimethoxy-quinazolin-2-yl)-methyl-amino]-methyl}-4-phenyl-piperidin-1-yl)-3-hydroxy-butan-1-one;
(R)-1-(4-{[(4-Amino-6,7-dimethoxy-quinazolin-2-yl)-methyl-amino]-methyl}-4-phenyl-piperidin-1-yl)-3-hydroxy-butan-1-one;
1-(4-{[(4-Amino-6,7-dimethoxy-quinazolin-2-yl)-methyl-amino]-methyl}-4-phenyl-piperidin-1-yl)-1-(tetrahydro-duran-2yl-methanone;
1-(4-{[(4-Amino-6,7-dimethoxy-quinazolin-2-yl)-methyl-amino]-methyl}-4-phenyl-piperidin-1-yl)-1-pyrrolidin-2-yl-methanone;
N2-(1-Cyclopropanesulfonyl-4-phenyl-piperidin-4-ylmethyl)-6,7-dimethoxy-N2-methyl-quinazoline-2,4-diamine;
4-{[(4-Amino-6,7-dimethoxy-quinazolin-2-yl)-methyl-amino]-methyl}-4-phenyl-piperidine-1-sulfonic acid dimethylamide;
1-(4-{[(4-Amino-6,7-dimethoxy-quinazolin-2-yl)-methyl-amino]-methyl}-4-phenyl-piperidin-1-yl)-butan-1-one;
1-[4-{[(4-Amino-6,7-dimethoxy-quinazolin-2-yl)-methyl-amino]-methyl}-4-(4-fluoro-phenyl)-piperidin-1yl]-butan-1-one:
1-(4-{[(4-Amino-6,7-dimethoxy-quinazolin-2-yl)-methyl-amino]-methyl}-4-phenyl-piperidin-1-yl)-1-phenyl-methanone;
4-{[(4-Amino-6,7-dimethoxy-quinazolin-2-yl)-methyl-amino]-methyl}-4-phenyl-piperidine-1-carboxylic acid pyridin-3-ylamide;
N2-[1-(2-Cyclopropyl-1-imino-ethyl)-4-phenyl-piperidin-4-ylmethyl]-6,7-dimethoxy-N2-methyl-quinazoline-2,4-diamine;
4-{[(4-Amino-6,7-dimethoxy-quinazolin-2-yl)-methyl-amino]-methyl}-N-methyl-4-phenyl-piperidine-1-carboxamidine; or
N2-[1-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-phenyl-piperidin-4-ylmethyl]-6,7-dimethoxy-N2-methyl-quinazoline-2,4-diamine.
Compounds of the present invention may be made by the methods depicted in the illustrative synthetic reaction schemes shown and described below.
The starting materials and reagents used in preparing these compounds generally are either available from commercial suppliers, such as Aldrich Chemical Co., or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser""s Reagents for Organic Synthesis; Wiley and Sons: New York, 1991, Volumes 1-15; Rodd""s Chemistry of Carbon Compounds, Elsevier Science Publishers, 1989, Volumes 1-5 and Supplementals; and Organic Reactions, Wiley and Sons: New York, 1991, Volumes 1-40. The following synthetic reaction schemes are merely illustrative of some methods by which the compounds of the present invention may be synthesized, and various modifications to these synthetic reaction schemes may be made and will be suggested to one skilled in the art having referred to the disclosure contained in this Application.
The starting materials and the intermediates of the synthetic reaction schemes may be isolated and purified if desired using conventional techniques including but not limited to filtration, distillation, crystallization, chromatography, and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.
Unless specified to the contrary, the reactions described herein preferably take place at atmospheric pressure over a temperature range from about xe2x88x9220xc2x0 C. to reflux, and most preferably at about room (or ambient) temperature, e.g., about 20xc2x0 C.
In general, the compounds of Formula (I) are prepared following the method described in Scheme A.
Scheme A describes a method of preparing a compound of Formula (I) wherein A, R1 and R2 are as described in the Summary of the Invention. 
A compound of Formula (I) can be prepared by reacting the free amine group of compound 2 (prepared according to DeGraw et al., J. Med. Chem. 1967, 10, 174) with a compound of formula 1 wherein L is a leaving group such as halogen, preferably chloro, optionally in the presence of a base such as sodium carbonate, potassium carbonate, diisopropylethylamine, tributylamine, or triethylamine, in an inert solvent such as lower alkanol, DMSO, or DMF, to obtain a compound 3. The benzyl group of compound 3 can be removed by procedures known to one skilled in the art to yield the free amino base 4. For example, a method of debenzylation can be carried out by hydrogenation. The hydrogenation is carried out with a suitable catalyst (e.g., 10% palladium on carbon (Pd/C), palladium hydroxide, palladium acetate, etc., preferably 10% Pd/C) in the presence of ammonium formate and in an appropriate solvent, typically an alcohol, preferably methanol, preferably at about 20xc2x0 C. to about 100xc2x0 C., and more preferably at reflux. Alternatively, the benzyl group can be removed by treating the protected compound with the catalyst under a hydrogen atmosphere at 1 to 50 psi, and preferably at approximately 15 psi, at about 20xc2x0 C. to about 100xc2x0 C., and preferably at about 20xc2x0 C. to about 60xc2x0 C. Compounds of Formula (I), where A is other than benzyl or hydrogen may be obtained from compound 4. Functionalizing the secondary nitrogen atom with an appropriate reagent by procedures known to one skilled in the art can form amides, ureas, carbamates, sulfonamides, guanidines, sulfamides and amidines of Formula (I).
Exemplary preparations of a compound of Formula (I) are given in Examples 1 to 13.
Alpha-1 adrenergic receptors mediate the contractile state of smooth muscle tissue and are present in the human prostate, bladder neck and urethra. Sympathetic activity produces contraction of vascular smooth muscle which leads to elevated blood pressures. Alpha-1 adrenergic receptor stimulation also produces glycogenolysis, growth and hypertrophy of cardiac myocytes and contraction of urethral and bladder neck smooth muscle, leading to increased resistance in urinary outflow. Thus, alpha-1 adrenoceptor antagonists may be useful in treating disorders or symptoms related to uropathies such as obstruction due to benign prostatic hyperplasia (BPH). (See U.S. Pat. No. 5,859,014; Lepor, H., The Prostate Supplement, 1990, 3, 75-84 and International Publication No. WO 95/25726.)
Experimental evidence supports a therapeutic role for alpha-1 adrenergic receptor antagonists in treating prostatic hyperplasia. (See for example, Lepor, H., The Prostate Supplement 1990, 3, 75-84.) Obstruction of the urinary tract can occur as a result of prostatic hyperplasia and excessive prostatic constriction of the urethra. This in turn leads to diminished urinary flow rates and an increased urgency and frequency of urination.
In a preferred embodiment, the compounds of this invention are useful for treating disease states which can be ameliorated by modulation, preferably by blockade of alpha-1 adrenoceptors, such as reduction or alleviation of urinary tract disorders, for example, pelvic hypersensitivity (including interstitial cystitis, prostatitis, pelvic pain syndrome, infectious cystitis, prostatodynia, and the like), overactive bladder, urinary frequency, nocturia, urinary urgency, detrusor hyperreflexia, outlet obstruction, prostatitis, urge incontinence, urethritis, idiophatic bladder hypersensitivity, and the like. Compounds of this invention may also be useful for treating male erectile dysfunction and female sexual dysfunction.
In a more preferred embodiment, the compounds of this invention are useful for treating disease states which can be ameliorated by blockade of alpha-1B adrenoceptors. Alpha-1B adrenoceptors are present in the liver, heart and cerebral cortex and are believed to be involved in mediating vascular contractile and blood pressure responses. Additionally, alpha-1B adrenoceptors are also present in areas of the spinal cord which receive input from sympathetic neurons originating in the pontine micturition center and are presumed to be involved in the regulation of bladder function. Selective blockade of the alpha-1B adrenoceptor may lead to the symptomatic treatment of pelvic hypersensitivity (including interstitial cystitis, prostatitis, pelvic pain syndrome, infectious cystitis, prostatodynia, and the like), urethritis, overactive bladder (manifested as urge incontinence), detrusor hyperreflexia, outlet obstruction (resulting from benign prostatic hypertrophy and prostatitis), and other conditions of idiopathic bladder hypersensitivity.
Additionally, alpha -1B adrenoceptor antagonists are useful as analgesic/antihyperalgesic therapies for treating pain, including symptoms of acute pain, inflammatory pain, neuropathic pain (including thermal and mechanical hyperalgesia as well as thermal and mechanical allodynia), complex regional pain syndromes (including reflex sympathetic dystrophy, causalgia and sympathetically maintained pain). (See, commonly owned U.S. patent application Ser. No. 09/521,185 by Ford et al. entitled xe2x80x9cA Method For Screening Compounds For Alpha-1B Adrenergic Receptor Antagonist and Analgesic Activity,xe2x80x9d filed on Mar. 17, 1999, the disclosure of which is hereby incorporated by reference in its entirety).
Additionally, alpha-1B adrenoceptor antagonists are useful for the treatment of CNS disorders including, but not limited to, general anxiety disorder, panic disorder, sleep disorders, posttraumatic stress disorder, and schizophrenia.
These and other therapeutic uses are described, for example, in Goodman and Gilman""s, The Pharmacological Basis of Therapeutics, ninth edition, McGraw-Hill, New York, 1996, Chapter 26:601-616; and Coleman, R. A., Pharmacological Reviews 1994, 46:205-229.
The pharmacology of the compounds of this invention was determined by art recognized procedures. The in vitro techniques for determining the affinities of test compounds at alpha-1 adrenoceptor subtypes in radioligand binding and functional assays are described in Example 21.
The effect of the compounds of this invention on blood pressure can be evaluated by any method known in the art. Examples of such methods are the Rat In Vivo Blood Pressure Assay, the Rat in Vivo Tilt-Response Assay, and the Dog In Vivo Blood and Intraurethral Pressure assay. An in vivo assay for measuring the blood pressure lowering effects of test compounds in normotensive rats is described in Example 22.
The analgesic activity of the compounds of this invention can be evaluated by any method known in the art. Examples of such methods are the Tail-flick test (D""Amour et al. J. Pharmacol Exp. and Ther. 1941, 72, 74-79), the Rat Tail Immersion Model, the Carrageenan-induced Paw Hyperalgesia Model, the Formalin Behavioral Response Model (Dubuisson et al., Pain 1977, 4, 161-174), the Von Frey Filament Test (Kim et al., Pain, 1992, 50, 355-363), the Chronic Constriction Injury, the Radian Heat Model, and the Cold Allodynia Model (Gogas et al., Analgesia, 1997, 3:111-118). An in vivo assay for measuring the effect of test compounds on the pain response to radiant heat in neuropathic rats is described in Example 23.
The potential of alpha-1 adrenoceptor antagonists to cause postural hypotension can be evaluated for example with the blood withdrawal model in conscious rat. An in vivo assay for measuring the effect of test compounds on postural hypotension in conscious rats is described in Example 24.
Preferred compounds of this invention generally demonstrate selectivity for the alpha 1B-subtype over the alpha-1A and alpha-1D subtype. The compounds of this invention may reduce both obstructive and irritative symptoms in patients with BPH. Additionally they may be useful in the treatment of pain or in the treatment of CNS disorders. The reduction of alpha-1A and alpha-1D adrenoceptor antagonism is expected to lead to reduced or fewer side effects than those associated with the use of non-subtype-selective agents.
The present invention includes pharmaceutical compositions comprising at least one compound of the present invention, or acceptable prodrug, salt or solvate thereof, together with at least one pharmaceutically acceptable carrier, and optionally other therapeutic and/or prophylactic ingredients.
In general, the compounds of the present invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. Suitable dosage ranges are typically 1-500 mg daily, preferably 1-100 mg daily, and most preferably 1-30 mg daily depending upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, the indication towards which the administration is directed, and the preferences and experience of the medical practitioner involved. One of ordinary skill in the art of treating such diseases will be able, without undue experimentation and in reliance upon personal knowledge and the disclosure of this Application, to ascertain a therapeutically effective amount of the compounds of the present invention for a given disease.
In general, compounds of the present invention will be administered as pharmaceutical formulations including those suitable for oral (including buccal and sub-lingual), rectal, nasal, topical, pulmonary, vaginal, or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation. The preferred manner of administration is generally oral using a convenient daily dosage regimen which can be adjusted according to the degree of affliction.
A compound or compounds of the present invention, together with one or more conventional adjuvants, carriers, or diluents, may be placed into the form of pharmaceutical compositions and unit dosages. The pharmaceutical compositions and unit dosage forms may be comprised of conventional ingredients in conventional proportions, with or without additional active compounds or principles, and the unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. The pharmaceutical compositions may be employed as solids, such as tablets or filled capsules, semisolids, powders, sustained release formulations, or liquids such as solutions, suspensions, emulsions, elixirs, or filled capsules for oral use; or in the form of suppositories for rectal or vaginal administration; or in the form of sterile injectable solutions for parenteral use. Formulations containing about one (1) milligram of active ingredient or, more broadly, about 0.01 to about one hundred (100) milligrams, per tablet, are accordingly suitable representative unit dosage forms.
The compounds of the present invention may be formulated in a wide variety of oral administration dosage forms. The pharmaceutical compositions and dosage forms may comprise a compound or compounds of the present invention or acceptable salt thereof as the active component. The pharmaceutically acceptable carriers may be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component. In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from about one (1) to about seventy (70) percent of the active compound. Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term xe2x80x9cpreparationxe2x80x9d is intended to include the formulation of the active compound with encapsulating material as carrier, providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges may be as solid forms suitable for oral administration.
Other forms suitable for oral administration include liquid form preparations including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations which are intended to be converted shortly before use to liquid form preparations. Emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions or may contain emulsifying agents, for example, such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents. Solid form preparations include solutions, suspensions, and emulsions, and may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
The compounds of the present invention may be formulated for parenteral administration (e.g., by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol. Examples of oily or nonaqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preserving, wetting, emulsifying or suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water.
The compounds of the present invention may be formulated for topical administration to the epidermis as ointments, creams or lotions, or as a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also containing one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Formulations suitable for topical administration in the mouth include lozenges comprising active agents in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
The compounds of the present invention may be formulated for administration as suppositories. A low melting wax, such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active component is dispersed homogeneously, for example, by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and to solidify.
The compounds of the present invention may be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
The compounds of the present invention may be formulated for nasal administration. The solutions or suspensions are applied directly to the nasal cavity by conventional means, for example, with a dropper, pipette or spray. The formulations may be provided in a single or multidose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomizing spray pump.
The compounds of the present invention may be formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration. The compound will generally have a small particle size for example of the order of five (5) microns or less. Such a particle size may be obtained by means known in the art, for example by micronization. The active ingredient is provided in a pressurized pack with a suitable propellant such as a chlorofluorocarbon (CFC), for example, dichlorodifluoromethane, trichlorofluoro-methane, or dichlorotetrafluoroethane, or carbon dioxide or other suitable gas. The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by a metered valve. Alternatively the active ingredients may be provided in a form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP). The powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form for example in capsules or cartridges of e.g., gelatin or blister packs from which the powder may be administered by means of an inhaler.
When desired, formulations can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient. For example, the compounds of the present invention can be formulated in transdermal or subcutaneous drug delivery devices. These delivery systems are advantageous when sustained release of the compound is necessary and when patient compliance with a treatment regimen is crucial. Compounds in transdermal delivery systems are frequently attached to an skin-adhesive solid support. The compound of interest can also be combined with a penetration enhancer, e.g., Azone (1-dodecylazacycloheptan-2-one). Sustained release delivery systems are inserted subcutaneously into to the subdermal layer by surgery or injection. The subdermal implants encapsulate the compound in a lipid soluble membrane, e.g., silicone rubber, or a biodegradable polymer, e.g., polylactic acid.
The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
Other suitable pharmaceutical carriers and their formulations are described in Remington: The Science and Practice of Pharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton, Pa. Representative pharmaceutical formulations containing a compound of the present invention are described in Examples 14-20.